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P Goudet,
C Bonithon-Kopp,
A Murat,
P Ruszniewski,
P Niccoli,
F Ménégaux,
G Chabrier,
F Borson-Chazot,
A Tabarin,
P Bouchard,
G Cadiot,
A Beckers,
I Guilhem, O Chabre,
P Caron,
H Du Boullay,
B Verges,
C Cardot-Bauters
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ABSTRACT: Multiple endocrine neoplasia type 1 (MEN1) disease is an autosomal dominant syndrome that is believed to equally affect men and women. This assumption has never been confirmed.
The aims of this study were to evaluate the impact of gender on the prevalence of MEN1 lesions, on their lifetime probability of occurrence, and on the diagnosis of MEN1.
Data regarding a study of 734 cases of MEN1 from the multicenter 'Groupe d'étude des Tumeurs Endocrines' were analyzed.
There were 57.8% females. The prevalence and probability of pancreatic tumors were higher in males than in females (P=0.06, P=0.0004). This difference was due to gastrinomas. The prevalence and probability of developing pituitary tumors were significantly greater in females (P<0.001, P<0.0001). Thymic tumors were exclusively found in men. There were no significant gender differences in the prevalence and the probability of developing hyperparathyroidism, or adrenal and bronchial tumors, or in the proportion of positive genetic tests. A family history of MEN1 was more frequently found in men than in women at the time of diagnosis (P=0.02). In the case of pituitary tumor, the proportion of patients diagnosed with MEN1 at the time of the first lesion was lower in women (44.2%) than in men (67.3%).
The phenotype expression of the MEN1 disease gene was different in males and females. In female patients, the possibility of MEN1 is not sufficiently taken into account. Any patient presenting a lesion that belongs to the MEN1 spectrum, such as a pituitary tumor, should be closely questioned about their family history and should be tested for hypercalcemia.
European Journal of Endocrinology 07/2011; 165(1):97-105. · 3.42 Impact Factor
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V Rohmer,
G Vidal-Trecan,
A Bourdelot,
P Niccoli,
A Murat,
J L Wemeau,
F Borson-Chazot,
C Schvartz,
A Tabarin, O Chabre,
G Chabrier,
P Caron,
P Rodien,
M Schlumberger,
E Baudin
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ABSTRACT: In hereditary medullary thyroid carcinoma (HMTC), prophylactic surgery is the only curative option, which should be properly defined both in time and extent.
To identify and characterize prognostic factors associated with disease-free survival (DFS) in children from HMTC families.
We conducted a retrospective analysis of a multi-center cohort of 170 patients below age 21 at surgery. Demographic, clinical, genetic, biological data [basal and pentagastrine-stimulated calcitonin (CT and CT/Pg, respectively)], and tumor node metastasis (TNM) status were collected. DFS was assessed based on basal CT levels. Kaplan-Meier curves, Cox regression, and logistic regression models were used to determine factors associated with DFS and TNM staging.
No patients with a preoperative basal CT <31 ng/ml had persistent or recurrent disease. Medullary thyroid carcinoma defined by a diameter ≥10 mm [hazard ratio (HR): 6.0; 95% confidence interval (95% CI): 1.8-19.8] and N1 status (HR: 20.8; 95% CI: 3.9-109.8) were independently associated with DFS. Class D genotype [odds ratio (OR): 48.5, 95% CI: 10.6-225.1], preoperative basal CT >30 ng/liter (OR: 43.4, 95% CI: 5.2-359.8), and age >10 (OR: 5.5, 95% CI: 1.4-21.8) were associated with medullary thyroid carcinoma ≥10 mm. No patient with a preoperative basal CT <31 ng/ml had a N1 status. Class D genotype (OR: 48.6, 95% CI: 8.6-274.1), and age >10 (OR: 4.6, 95% CI: 1.1-19.0) were associated with N1 status.
In HMTC patients, DFS is best predicted by TNM staging and preoperative basal CT level below 30 pg/ml. Basal CT, class D genotype, and age constitute key determinants to decide preoperatively timely surgery.
The Journal of clinical endocrinology and metabolism 12/2010; 96(3):E509-18. · 6.50 Impact Factor
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P Chanson,
J Bertherat,
A Beckers,
H Bihan,
T Brue,
P Caron, O Chabre,
M Cogne,
C Cortet-Rudelli,
B Delemer,
H Dufour,
R Gaillard,
M Gueydan,
I Morange,
J-C Souberbielle,
A Tabarin
Annales d Endocrinologie 05/2009; 70(2):92-106. · 0.74 Impact Factor
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A Tabarin,
S Bardet,
J Bertherat,
B Dupas, O Chabre,
E Hamoir,
F Laurent,
F Tenenbaum,
M Cazalda,
H Lefebvre,
N Valli,
V Rohmer
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ABSTRACT: The French Society of Endocrinology convened a multidisciplinary panel of endocrinologists, radiologists, nuclear physicians and surgeons to address the appropriate evaluation and treatment of adrenal incidentalomas. The panel conducted a systematic review of medical literature on the following issues: epidemiology, natural history, radiological and scintigraphic evaluation, endocrine assessment, surgical management and appropriate follow-up. The following text reports the recommendations of experts on behalf of the French Society of Endocrinology. The authors emphasize the paucity of published scientific data that hampers evidence-based medicine recommendations. The crucial points of the French consensus are: the usefulness of CT-scanning evaluation of adrenal incidentalomas, the systematic screening for pheochromocytoma, the usefulness of the 1mg overnight dexamethasone test to screen for latent hypercortisolism, the difficulty to interpret mild biological abnormalities of the HPA axis, the consensus to remove surgically most of tumours greater than 4cm, the necessity to follow clinically glucorticoid tissular targets in the follow-up of non operated benign adrenocortical incidentalomas.
Annales d Endocrinologie 12/2008; 69(6):487-500. · 0.74 Impact Factor
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ABSTRACT: Medical treatment of hyperprolactinemia is based upon use of dopamine agonists (DA): bromocriptine, lisuride, quinagolide and cabergoline. In over 80% of cases, these drugs induce normal prolactinemia and ovulatory cycles. In resistant cases, the DA should be changed. Tolerance may occasionally be poor, particularly with bromocriptine, which appears less well-tolerated than quinagolide and than cabergoline above all. In the event of intolerance to a given DA, another should be tried. In patients with macroprolactinoma treated with DA, MRI monitoring should be carried out after 3 months of treatment to verify tumor size reduction, then after 1 year, yearly for the next 5 years and once every 5 years if adenoma size is stable. In cases of microprolactinoma, control under treatment is pointless. MRI may be performed after 1 year and then after 5 years. Once normal prolactin levels have been achieved, attempts may be made to stop the treatment. When a prolonged treatment is interrupted, especially with cabergoline, progressive increase in serum prolactin and return of hyperprolactinemia symptoms are seen in only around 20-30% of cases, particularly when residual adenoma exists after prolonged treatment. Nevertheless, prolactin levels should continue to be monitored after discontinuation of DA, possibly with MRI monitoring, since prolactin levels may rise again after a number of months or years. When normal prolactin levels have been achieved with DA, another solution consists in reducing the dose or dosing frequency of DA in steps to the lowest effective dose consistent with maintenance of normal prolactin levels and stable adenoma size. For drug-induced hyperprolactinemia, where the causative medication cannot be withdrawn, it is often pointless and possibly even dangerous to administer a DA. It is therefore necessary to check for absence of pituitary adenoma and where necessary, begin treatment with sex steroids so as to ensure satisfactory impregnation with sex steroids and avoid osteoporosis. For macroprolactinoma, the first-line treatment is drug therapy with DA. At present, there is no evidence to suggest that prior treatment with DA can modify the outcome of surgery. With microprolactinoma, DA treatment offers a good first-line therapeutic option but surgery may also be useful. DAs for microprolactinoma may be withdrawn after menopause.
Annales d Endocrinologie 07/2007; 68(2-3):113-7. · 0.74 Impact Factor
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ABSTRACT: Aberrant expression of G protein-coupled receptors (GPCR) in the adrenal cortex is observed in some cases of ACTH-independent macronodular adrenal hyperplasias and adenomas associated with Cushing syndrome (CS). Although there is clinical evidence for the implication of these receptors in abnormal regulation of cortisol secretion, whether this aberrant expression also directly causes the development of a benign adrenocortical tumor is an open question. Cell transplantation provides a way to study genes that may be important in human tumor development. The system we developed uses genetically modified adrenocortical cells transplanted into adrenalectomized immunodeficient mice, which form a functional tissue structure. We observed that enforcing expression of the gastric inhibitory polypeptide (GIP) receptor or the luteinizing hormone (LH) receptor genes (taken as canonical examples of aberrantly expressed GPCRs) in adrenocortical cells resulted in the formation of hyperplastic tissues and the development of Cushing syndrome features in transplanted mice.
Molecular and Cellular Endocrinology 03/2007; 265-266:23-8. · 4.19 Impact Factor
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ABSTRACT: The prevalence and characteristics of patients operated for adrenal adenoma (Conn syndrome) as well as their post-operative arterial pressure evolution are varying through literature. Our aim was to report the Grenoble University Hospital experience. From 1993 to 2005, 24 patients (mean age = 46 +/-11 years) presented the biological criteria of primary hyperaldosteronism and benefited from adrenalectomy with confirmation of adrenal adenoma. All had an uncontrolled hypertension, refractory in 42% of cases, with a hypokaliemia (mean = 2.65 +/- 0.47 mmol/l). All adenomas measured more than 10 mm in scanner imaging. After a mean post-operative follow-up of 46 +/- 43 months, 70% of them were normotensive, with (45%) or without (25%) anti-hypertensive therapy. the post-operative kaliemia was normal in all cases. Only 25% had post-operative hormonal dosages for control. Post-operative spontaneous normotensive patients had, at the diagnosis of adrenal adenoma, a more recent and non-refractory hypertension, with a lower number of antihypertensive drugs, a better response to spirinolactone and higher aldosterone plasmatic levels. Two lessons can be taken from this study: 1) Whether 70% of patients operated for adrenal adenoma are normotensive (with or without treatement) post-operatively, only 25% are definitely cured after 4 years. Factors associated to a post-operative cure highlight the interest of an ealy diagnosis. 2) There is probably an underdiagnosis of adrenal adenoma (Conn syndrome) because neither adenomas with normokaliemia, nor adenomas <10 mm in scanner imaging have ever been diagnosed or at least, sent to surgery.
Archives des maladies du coeur et des vaisseaux 03/2007; 100(2):121-5. · 0.40 Impact Factor
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Annales D Endocrinologie - ANN ENDOCRINOL. 01/2004; 65(4):263-264.
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F De Fraipont,
G Le Moigne,
G Defaye,
M El Atifi,
F Berger,
R Houlgatte,
C Gicquel,
P F Plouin,
X Bertagna, O Chabre,
J J Feige
Endocrine Research 12/2002; 28(4):785-6. · 0.97 Impact Factor
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ABSTRACT: ACTH assay in cavernous sinus samples during resection of pituitary adrenocorticotroph adenomas is a simple and safe technique providing an intraoperative assessment of adrenocorticotroph hormone gradients. Bilateral puncture of the cavernous sinus can be achieved vial the standard transsphenoidal approach to the sella turcica. ACTH is determined with IRMA at 37;C with an incubation time of less than one hour. Among 71 cases in our experience, the ACTH gradient accurately predicted the position of the adenoma in 93% of the cases. This rate is higher than the 61% accuracy reported for inferior petrosal sinus sampling. The technique reported is more precise than MRI which correctly identifies adenomas in only 50% of the cases. The remaining cases are either false positives or false negatives. We report an 82% cure rate either via direct resection of the microadenoma or via partial hypophysectomy guided by the ACTH gradient. In our series, 20 cases of Cushing's disease had a normal MRI and no surgically identifiable adenoma. In 10 of these cases however, cure was achieved by performing ACTH gradient guided partial hypophysectomy. This method produces no morbidity and is most helpful for the neurosurgeon allowing confirmation of the position of an MRI-visible adenoma or an adenoma identified intraoperatively. It does not however replace neurosurgical experience which remains the most important predictive factor for outcome in surgical treatment of Cushing's disease.
Neurochirurgie 06/2002; 48(2-3 Pt 2):223-5. · 0.34 Impact Factor
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ABSTRACT: Loss of heterozygosity for polymorphic markers flanking the multiple endocrine neoplasia type 1 (MEN-1) gene in parathyroid and pancreatic islet tumours from subjects with MEN-1 has been well documented and has led to the hypothesis that the MEN-1 gene functions as a recessive tumour suppressor gene. We report a case of MEN-1 with duodeno-pancreatic gastrinoma, parathyroid hyperplasia, pituitary adenoma, adrenal adenoma, and lipomas, whose rare association with a malignant gastrointestinal stromal tumour (GIST) represents an undescribed combination. MEN-1 mutation in this family was shown as a frameshift (1607delA) in exon 10. To assess the role of the MEN-1 gene in the pathogenesis of tumours less commonly associated with MEN-1, we studied GIST DNA for loss of the unaffected MEN-1 gene allele. Stromal tumour and peripheral leucocyte DNAs from our patient were examined for loss of heterozygosity using the PYGM microsatellite polymorphism and an intragenic polymorphism (D418D in exon 9) in the MEN-1 gene. We showed no evidence for loss of the wild-type MEN-1 allele in GIST. The MEN-1 germline inactivating mutation 1607delA-ter558 in exon 10 was detected in the stromal tumour DNA, but no somatic mutation in the wild-type MEN-1 allele in GIST DNA was detected. Occurrence of GIST could be consistent with the possibility that this MEN-1-related uncommon neoplasm arose independently by a mechanism unrelated to the MEN-1 gene.
European Journal of Gastroenterology & Hepatology 03/2001; 13(2):207-11. · 1.76 Impact Factor
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L Nguyen,
P Niccoli-Sire,
P Caron,
D Bastie,
B Maes,
G Chabrier, O Chabre,
V Rohmer,
P Lecomte,
J F Henry,
B Conte-Devolx
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ABSTRACT: The aim of this prospective study is to update our knowledge of the chronology of pheochromocytoma occurrence in multiple endocrine neoplasia type 2 (MEN 2), and to better manage MEN 2 patients after the genetic diagnosis.
Eighty-seven non-index gene carrier MEN 2 patients were included in this prospective study: 84 patients with MEN 2A (from 52 families) and 3 with MEN 2B (from 3 families).
Medullary thyroid carcinoma (MTC) was diagnosed by measuring plasma calcitonin in basal conditions or after pentagastrin stimulation. The search for pheochromocytoma consisted of clinical evaluation, 24 h determination of urinary catecholamines and adrenal imaging. The mean age at genetic diagnosis of MEN 2 was 14.0+/-7.0 years, the mean duration for the follow-up was 7.6+/-2.8 years.
All 87 patients had a MTC detected at the same time as the genetic diagnosis was made. Urinary catecholamine measurements led to the diagnosis of pheochromocytoma and a combination of imaging techniques enabled the correct localization of both unilateral or bilateral adrenal involvement. Pheochromocytoma was detected simultaneously with MTC in only seven patients, and seven others were detected throughout the follow-up. Of the 14 patients with pheochromocytoma, 11 had bilateral involvement: nine were initially bilateral and two became so during follow-up.
This study demonstrates that in MEN 2, MTC is the lesion which appears earliest. Pheochromocytoma develops later during the evolution of the disease, and necessitates regular clinical and biological monitoring throughout follow-up. Determination of urinary and/or plasma catecholamines and metanephrines should be performed to detect pheochromocytoma. Imaging techniques lead to the detection of both unilateral and bilateral pheochromocytoma, thus making video-assisted laparoscopic adrenalectomy possible.
European Journal of Endocrinology 02/2001; 144(1):37-44. · 3.42 Impact Factor
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ABSTRACT: We present an in vivo and in vitro study of congenital adrenal hyperplasia in a patient with 11beta-hydroxylase deficiency. Sequencing of the CYP11B1 gene showed two new base substitutions, a conservative 954 G-->C transversion at the last base of exon 5 (T318T), and a IVS8 + 4A-->G transition in intron 8. In addition, two polymorphisms were found in exons 1 and 2. The genetically female patient was raised as a male because of severe pseudohermaphroditism. Glucocorticoid-suppressive treatment encountered difficulties in equilibration and compliance, resulting in uncontrolled hypertension with pronounced hypertrophic cardiomyopathy. At 42 yr of age the occurrence of central retinal vein occlusion with permanent loss of left eye vision led to the decision to perform bilateral laparoscopic adrenalectomy. Surgery was followed by normalization of blood pressure and good compliance with glucocorticoid and androgen substitutive therapies. In vitro, adrenal cells in culture and isolated mitochondria showed extremely low 11beta-hydroxylase activity. Analysis of adrenal CYP11B1 messenger ribonucleic acid (mRNA) by RT-PCR and sequencing showed the expression of a shorter mRNA that lacked exon 8 and did not contain either the exon 5 mutation or the exon 1 and 2 polymorphisms. This suggested that one CYP11B1 allele carried the intron 8 mutation, responsible for skipping exon 8. The other allele carried the exon 5 mutation, and its mRNA was not detectable. Western blot analysis showed weak expression of a shorter CYP11B immunoreactive band of 43 kDa, consistent with truncation of exon 8. Thus, bilateral adrenalectomy in this patient allowed effective treatment of severe hypertension and helped in understanding the mechanisms and physiopathological consequences of two novel mutations of CYP11B1.
Journal of Clinical Endocrinology & Metabolism 12/2000; 85(11):4060-8. · 6.50 Impact Factor
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ABSTRACT: We present an in vivo and in vitro study of congenital adrenal hyperplasia in a patient with 11beta-hydroxylase deficiency. Genetic analysis showed two new base substitutions of CYP11B1, a conservative transition at the last base of exon 5, and a IVS8+4A-->G transition in intron 8. Difficulties with suppressive therapy resulted in severe hypertension. A laparoscopic adrenalectomy was decided which lead to normalization of blood pressure. In vitro, steroidogenesis by adrenal cells showed no measurable 11beta-hydroxylase activity. Analysis of CYP11B1 mRNA by RT-PCR and sequencing showed expression of a mRNA which lacked exon 8, presumably resulting from the intron 8 mutation. In addition a highly truncated mRNA was detected corresponding to exons 1, 2, 8, 9, with the loss of exons 3-7, presumably related to the exon 5 mutation. Western blot analysis showed a shorter CYP11B immunoreactive band of 43 kDa, consistent with truncation of exon 8. Thus adrenalectomy in this patient allowed effective treatment of severe hypertension and helped to understand the mechanisms of two novel mutations responsible for aberrant splicing of CYP11B1.
Endocrine Research 11/2000; 26(4):797-801. · 0.97 Impact Factor
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Journal of Clinical Endocrinology & Metabolism 10/1999; 84(9):3401-2. · 6.50 Impact Factor
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Clinical Nuclear Medicine 07/1999; 24(6):459-60. · 3.67 Impact Factor
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F Labat-Moleur, O Chabre,
C Guillermet,
P Chaffanjon,
F Blumet-Rondeu,
A Bauchet,
B Franc,
E Brambilla,
I Bachelot,
J E Dumont,
A Negoescu
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ABSTRACT: This study demonstrates the involvement of a Bax-Bcl2-dependent apoptotic process in Graves-Basedow thyroid disease, a pathological condition known for its spontaneously oscillating evolution. A continuous series of 86 cases of surgically treated Graves' thyroid was evaluated for apoptotic cell content identified by histological criteria and confirmed by terminal desoxynucleotidyl transferase-mediated desoxyuridine triphosphate nick end-labeling (TUNEL). A significant correlation was found between tissue features of Graves' disease (epithelial hyperplasia, cellular hypertrophy, colloid content) and the amount of apoptotic cells. No correlation was found with lymphocytic infiltrates. Significantly, 11 cases (about 12% of the series) with high-level apoptosis displayed the typical features of active Graves' disease over all tissue sections. In contrast, cases with no detectable apoptosis exhibited regressive tissue features of Graves' disease. An intermediate group of cases was characterized by tissue heterogeneity with hyperactive foci, rich in apoptosis, alternating with regressive areas lacking apoptosis. In this group the participation of apoptosis to the remodeling of Graves' thyroid parenchyma, in a tight balance with cell proliferation, was best illustrated. Moreover, the thyroid follicle by accumulating apoptotic cells and bodies, allowed a tentative chronological ordering of apoptosis steps in correlation with Bax-Bcl2 tissue distribution and cellular pattern. Our observations suggest that the initiation of apoptosis corresponds to a loss of cellular cohesion, a drop in Bcl2 expression, and a delocalization of Bax from a putative Golgi storage location to a mitochondrial distribution.
Thyroid 06/1999; 9(5):483-92. · 4.79 Impact Factor
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N Beressi,
J M Campos,
J P Beressi,
B Franc,
P Niccoli-Sire,
B Conte-Devolx,
A Murat,
P Caron,
L Baldet,
J L Kraimps,
R Cohen,
J C Bigorgne, O Chabre,
P Lecomte,
E Modigliani
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ABSTRACT: Clinical characteristics and prognosis of 80 patients (53 women and 27 men) with sporadic medullary thyroid carcinomas (MTC), less than 1 cm in size (micro-MTC), operated on between 1971 and 1996 are reported (73 total and 7 partial thyroidectomies). These patients, obtained from a national database of 899 patients with MTC, were compared with 357 cases of sporadic MTC greater than 1 cm and 149 subjects with familial MTC less than 1 cm (familial micro-MTC). Median age at surgery was 52.5 years, a distribution similar to larger sporadic MTC. Micro-MTC was identified due to elevated calcitonin (47.5%), clinically identified lymph node (10.0%), distant metastases (6.3%) or pathologic finding at surgery (36.2%). Diarrhea and/or flushing were observed in 6 patients including 4 with clinically identified lymph node. Among patients who had lymph node dissection at surgery (68.8%), lymph node involvement with tumor was observed in 30.9%, and was significantly more frequent in multifocal (7/11) than in unifocal micro-MTC (p < 0.03). All sporadic micro-MTC were unilateral. Survival rate was 93.9% +/- 4.4% (SE) at 10 years, greater than that observed in sporadic macro-MTC (p = 0.04). Normal postoperative basal calcitonin (CT) was obtained in 71.1% of micro-MTC patients versus 33.6% in sporadic macro-MTC (p < 0.01). Sporadic micro-MTC is much more frequent than expected, 15% of MTC in our series. Although specific survival rate and percentage of biological cure in micro-MTC are significantly better than for larger tumors, the frequency of lymph node involvement, however, justifies an aggressive surgical approach including total thyroidectomy and bilateral central lymph node dissection.
Thyroid 12/1998; 8(11):1039-44. · 4.79 Impact Factor
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O Chabre,
P Liakos,
J Vivier,
P Chaffanjon,
F Labat-Moleur,
M Martinie,
S P Bottari,
I Bachelot,
E M Chambaz,
G Defaye,
J J Feige
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ABSTRACT: We studied a patient with food-induced, ACTH-independent, Cushing's syndrome and a unilateral adrenocortical adenoma. In vivo cortisol secretion was stimulated by mixed, glucidic, lipidic, or proteic meals. Plasma ACTH levels were undetectable, but iv injection of ACTH stimulated cortisol secretion. Unilateral adrenalectomy was followed by hypocortisolism with loss of steroidogenic responses to both food and ACTH. In vitro, cortisol secretion by isolated tumor cells was stimulated by the gut hormone gastric inhibitory polypeptide (GIP) and ACTH, but not by another gut hormone, glucagon-like peptide-1 (GLP-1). Both peptides stimulated the production of cAMP but not of inositol 1,4,5-trisphosphate. In quiescent cells, GIP and ACTH stimulated [3H]thymidine incorporation and p42-p44 mitogen-activated protein kinase activity. GIP receptor messenger ribonucleic acid (RNA), assessed by RT-PCR, was highly expressed in the tumor, whereas it was undetectable in the adjacent hypotrophic adrenal tissue, in two adrenal tumors responsible for food-independent Cushing's syndrome, and in two hyperplastic adrenals associated with ACTH hypersecretion. In situ hybridization demonstrated that expression of GIP receptor RNA was confined to the adrenocortical tumor cells. Low levels of ACTH receptor messenger RNA were also detectable in the tumor. We conclude that abnormal expression of the GIP receptor allows adrenocortical cells to respond to food intake with an increase in cAMP that may participate in the stimulation of both cortisol secretion and proliferation of the tumor cells.
Journal of Clinical Endocrinology & Metabolism 10/1998; 83(9):3134-43. · 6.50 Impact Factor
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S Giraud,
C X Zhang,
O Serova-Sinilnikova,
V Wautot,
J Salandre,
N Buisson,
C Waterlot,
C Bauters,
N Porchet,
J P Aubert, [......],
M Vallotton,
G Lenoir,
P Gaudray,
C Proye,
B Conte-Devolx,
P Chanson,
Y Y Shugart,
D Goldgar,
A Murat,
A Calender
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ABSTRACT: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome predisposing to tumors of the parathyroid, endocrine pancreas, anterior pituitary, adrenal glands, and diffuse neuroendocrine tissues. The MEN1 gene has been assigned, by linkage analysis and loss of heterozygosity, to chromosome 11q13 and recently has been identified by positional cloning. In this study, a total of 84 families and/or isolated patients with either MEN1 or MEN1-related inherited endocrine tumors were screened for MEN1 germ-line mutations, by heteroduplex and sequence analysis of the MEN1 gene-coding region and untranslated exon 1. Germ-line MEN1 alterations were identified in 47/54 (87%) MEN1 families, in 9/11 (82%) isolated MEN1 patients, and in only 6/19 (31.5%) atypical MEN1-related inherited cases. We characterized 52 distinct mutations in a total of 62 MEN1 germ-line alterations. Thirty-five of the 52 mutations were frameshifts and nonsense mutations predicted to encode for a truncated MEN1 protein. We identified eight missense mutations and five in-frame deletions over the entire coding sequence. Six mutations were observed more than once in familial MEN1. Haplotype analysis in families with identical mutations indicate that these occurrences reflected mainly independent mutational events. No MEN1 germ-line mutations were found in 7/54 (13%) MEN1 families, in 2/11 (18%) isolated MEN1 cases, in 13/19 (68. 5%) MEN1-related cases, and in a kindred with familial isolated hyperparathyroidism. Two hundred twenty gene carriers (167 affected and 53 unaffected) were identified. No evidence of genotype-phenotype correlation was found. Age-related penetrance was estimated to be >95% at age >30 years. Our results add to the diversity of MEN1 germ-line mutations and provide new tools in genetic screening of MEN1 and clinically related cases.
The American Journal of Human Genetics 08/1998; 63(2):455-67. · 10.60 Impact Factor
